Summary. Lyme Disease cases have increased more than 200% in the last decade. Antibiotic therapy is often effective, though many patients experience long-lasting complications, and it is not yet known why some patients develop chronic arthritis and neurologic involvement. Borrelia burgdorferi senso lato, the agent that causes Lyme Disease, is carried by the tick vector Ixodes scapularis. In addition to transmitting Lyme Disease I. scapularis carries and transmits other microorganisms, including species of Ehrlichia, Babesia, Anaplasma, as well as viral pathogens. This is significant as patients with tick-borne co-infections often exhibit more severe symptoms. It is currently unclear how the host innate immune system handles multiple pathogen types simultaneously. We propose to examine the impact of early innate myeloid cells on control of B. burgdorferi in mice co-infected with pathogens that are also transmitted by I. scapularis. Based on preliminary data we hypothesize that co-infecting pathogens elicit myeloid responses that are not able to control B. burgdorferi infection and result in enhanced dissemination. This is important because preventing dissemination reduces the probability of developing chronic disease. Our preliminary data demonstrate reduced blood neutrophils and platelets in mice co-infected with both Bb and an intracellular organism Ehrlichia muris, relative to mice infected with B. burgdorferi alone. We propose two related, but independent aims. In Aim 1 we will investigate the specific role of neutropenia, induced by co-infection, on B. burgdorferi dissemination. In Aim 2 we address the impact of thrombocytopenia and platelets on B. burgdorferi dissemination. This proof-of-concept work will address how infection with one pathogen enhances the infection, and dissemination, of another pathogen during tick-borne co-infection. Enhanced dissemination and infection of such tissues as the brain and heart are critical early events that induce susceptibility to long term complications. Information learned from these studies will define mechanisms of host defense against tick-borne co-infection, and may ultimately lead to novel therapies to prevent B. burgdorferi dissemination, which will reduce long-term complications such as carditis and arthritis.